Pediatric Thrombosis and Hemostasis

This and a following issue of Seminars in Thrombosis and Hemostasis are dedicated to the work of Dr. Maureen Andrew, whose pioneering and outstanding contributions have laid the foundation for a better understanding of the hemostasis system in children, for a better appreciation of bleeding disorders in children, and for recognizing the importance of thromboembolic disorders in children, once believed to be extremely rare in childhood.

Part 1 addresses the physiological aspects of the hemostasis system in children, its development, the fibrinolytic system, the protein C pathway, and platelet function. In addition, the problems of venous and arterial thromboembolic events in childhood are reviewed, including their clinical presentation and diagnostic aspects. Special consideration is given to arterial ischemic strokes and the impact of prothrombotic disorders on children's development. The peculiarities of anticoagulant therapy in children are also comprehensively discussed.

In the first article, Kuhle and associates review the developmental aspects of the hemostasis system with regard to pro- and anticoagulant factors. Much of this information was gathered by Dr. Maureen Andrew. The technical difficulties of this work, especially the limited quantity of blood that can be obtained from neonates, particularly prematures, were overcome when microassays became available. In healthy newborns most of the procoagulant factors are about one-half of adult values. This is reflective of the immaturity of the liver at that stage of development. These factor levels increase as the infants grow older. This developmental aspect can be further traced by analyzing blood from fetuses at various ages. The same trend can be seen when studying premature infants. A few factors, such as fibrinogen, von Willebrand factor, factor VIII, and factor XIII, are normal at birth and during infancy. Similar observations are made when the levels of the physiological regulators of the clotting system are analyzed. All inhibitors are at about half-normal levels at birth and in early childhood, but increase with age. Despite the reduced levels of pro- and anticoagulant factors, healthy neonates do not display a major bleeding or thrombosing tendency. If there are problems of this nature, and laboratory assays are performed, it is important to take age-related “normal” values into consideration, and for this reason, this review provides valuable information and guidelines.

The second contribution, by Albisetti, describes the fibrinolytic system in children. The author first reviews the components of the system in adults and then delineates these in healthy children. Considerable information exists on these factors in healthy newborns, in premature infants, and in children age 1 to 16 years. As with many other clotting factors, fibrinolytic proteins are found in lower concentrations at birth than in adults. This is particularly true for plasminogen and α₂-antiplasmin. Activators, such as tissue-type plasminogen activator and urokinase-type plasminogen activator, are at birth either elevated or normal. The same holds true for the regulators of the system, plasminogen activator inhibitor-1 and α2-macroglobulin. With all of these components there are differences, however, when measured in cord blood or in blood directly obtained from the infant. The overall fibrinolytic potential in children at an early age appears to be decreased due to the limited amounts of plasminogen. Albisetti also reviews the fibrinolytic system in children with a variety of disease states, and impaired fibrinolysis seems to play a major role in many. Information on thrombolytic therapy in children is limited and special attention must be given to the levels of plasminogen. This overview should provide readers with valuable information.

The protein C pathway in infants and children is comprehensively reviewed by Petäjä and Manco-Johnson. This pathway is not only a regulatory mechanism for the clotting system, but also modulates inflammation, as expertly outlined by the authors. At birth, protein C and protein S levels, like antithrombin, are considerably lower than adult levels; they reach normal ranges within the first 4 years of life. Interestingly, levels of α₂-macroglobulin and α1-antitrypsin, both of which inactivate thrombin, are higher in neonates than in adults. Less is known about the other components of the protein C pathway, thrombomodulin and endothelial protein C receptor. Congenital defects in protein C and protein S are associated with serious thrombotic complications, especially in homozygotes. Purpura fulminans neonatorum is an example of the devastating consequences of these particular defects. Heterozygous defects are rarely associated with thromboembolism during childhood, although the risk increases greatly after puberty. Combined risk factors pose a serious risk for thromboembolism during childhood, but routine testing of neonates born from parents with congenital defects in the protein C pathway is not advocated.

Israels and coworkers describe platelet function in neonates. Healthy newborns have normal platelet counts, normal megakaryopoiesis, and normal thrombopoietin levels. Also, the ultrastructure of neonatal platelets is not different from that of adults. There are, however, fewer surface receptors on neonatal platelets that could account for the decreased response to several stimuli. Measurements of platelet function have been hampered by limited blood volumes available from children. Bleeding times, although difficult to assess, appear to be shorter in neonates and measurements on in vitro bleeding time devices have also shown this shortening. This may be due to the higher hematocrits and the higher activities of von Willebrand factor. Platelet aggregation studies have yielded differing results, although, generally, neonatal platelets respond more slowly to most agonists, suggesting that platelets from neonates are hyporeactive. Considerable information exists on flow cytometry of neonatal platelets, again revealing hypo-reactivity. The reduced adhesibility and aggregability of neonatal platelets appears to be due to impaired receptor-mediated signal transduction. Most of the data described relate to healthy neonates. Very little is known about platelet function in premature or neonates at risk, and much of this information awaits further study. This essay by Israels and coworkers gives an excellent overview of platelets in neonates.

Sutor discusses the issue of vitamin K prophylaxis in newborns. Although vitamin K-deficiency bleeding (VKDB) is rare and predominantly observed in breast-fed infants, its development is unpredictable and often life-threatening. For this reason, vitamin K prophylaxis has been exercised for many years. Problems were, however, encountered, initially with the water-soluble, synthetic vitamin K₃ that caused hemolysis. While the intramuscular administration was the most effective prophylaxis, concerns were raised about the development of early childhood cancers. Late occurrence of VKDB was another problem, but this is likely due to inadequate prophylaxis. There appears to be sufficient evidence that general prophylaxis of newborns with vitamin K is needed to avoid this serious bleeding complication. Although recent data refute the assumption of a relationship between intramuscularly administered vitamin K prophylaxis and early childhood cancer, oral prophylactic use of vitamin K seems to work well, provided the dose and timing are considered. Several dosing schemes are presented that should be helpful to those interested in this issue.

In the next article Male and associates comprehensively review the problems of diagnosing venous thromboembolic diseases in children. Most of these disorders present in the central upper venous system and are often not recognized due to lack of symptoms or due to underlying diseases. Many are caused by central venous lines, as outlined in other articles in this issue. Only screening by objective radiographic techniques will often identify these thromboses. For diagnosing venous thromboses in the upper venous system, the combination of venography and ultrasound is required. If ultrasound identifies a thrombus, anticoagulation should commence immediately. Only when ultrasound plus venography are negative can thrombosis be ruled out. It is uncertain whether ultrasound alone is sufficient for diagnosing thrombosis in the lower central venous system in children. Magnetic resonance venography will likely improve the diagnostic capabilities greatly. All radiographic techniques are reviewed by the authors and advantages and disadvantages are clearly delineated.

Van Ommen and Peters review the issue of venous thromboembolism (VTE) in children. While venous thromboembolism is relatively rare in children, it is associated with a high degree of morbidity and mortality, especially in very young children. Of the many underlying clinical conditions leading to VTE, the majority develop as a consequence of indwelling catheters. Therefore most venous thomboses are located in the upper central venous system. Ultrasonography is most commonly employed to diagnose them, although other radiological techniques are also used. Congenital prothrombotic states, such as factor V Leiden, the prothrombin gene mutation, and deficiencies of natural inhibitors of the clotting system may also contribute to VTE in children. The issue of routine testing for these disturbances is addressed. While thromboprophylaxis is well accepted for adults, no large clinical studies are as yet available to guide healthcare providers in their decision-making for children. As with prophylactic use of anticoagulants, treatment options lack large prospective randomized trials in children. Guidelines are thus based on small studies or on extrapolation of data from adult trials. The trend for treatment of VTE in children also is in the direction of low-molecular-weight heparins (LMWH), which are easier to administer and control. For long-term treatment with oral anticoagulants, monitoring presents a special problem in the pediatric population.

Nowak-Göttl and colleagues review arterial ischemic strokes in neonates, infants, and children. Strokes in childhood are not uncommon and there are a variety of underlying disorders that provoke these events: cardiac diseases, sickle cell disease, infections, and collagen tissue abnormalities are only a few examples. Most children have cerebrovascular disorders, but congenital or acquired thrombophilic conditions may also contribute. The authors describe the clinical manifestations of pediatric strokes, the methods of diagnosis, and differential diagnoses. In comparison with adults, ischemic stroke in children has a better outcome. The various treatment options for these patients are also reviewed in some detail. This comprehensive review should enable readers to gain a thorough appreciation of this not so rare but serious pediatric problem.

In the next article, Golomb discusses the impact of prothrombotic disorders on peri- and neonatal strokes. Arterial ischemic infarcts and sinovenous thrombosis may result in strokes. Neonates appear to have a higher incidence than older children. There are many factors that relate to this disorder: thrombosis and infarctions in the placenta leading to emboli in the fetus, changes in the maternal hemostasis system leading to hypercoagulability and potential strokes, acquired and congenital hemostasis defects causing strokes in mothers and infants, cardiac malformations, and a variety of additional risk factors. These are comprehensively reviewed by the author. Prophylaxis can be administered when an underlying disorder is identified, as for example in patients with sickle cell disease, hyperhomocysteinemia, antiphospholipid syndrome, and congenital defects of inhibitors of the clotting system. Treatment of neonatal strokes consists predominantly of supportive measures. Not much information exists on the use of anticoagulants.

In the last contribution, Revel-Vilk and Chan examine the issues related to anticoagulant therapy in children. When using anticoagulants in children, especially in young ones, the developmental status of the hemostasis system has to be taken into consideration, especially the capacity to generate thrombin. Differences, compared with adults, could impact the dose of anticoagulants used. Unfortunately there are not many clinical studies in which different anticoagulants were tested in different age-related groups of children. Therefore, most guidelines are based on extrapolation from adult data. Both unfractionated heparin and LMWH are being used to treat children with thromboembolic complications. Resistance to heparins may, for example, be caused by physiologically low antithrombin levels. Bleedings and heparin-induced thrombocytopenia are concerns when using unfractionated heparin; they are of less concern when LMWH are used. The authors provide guidelines for treating children with both types of heparin. With the use of oral anticoagulants, not much information can be found on the proper international normalized ratio to be achieved. Again, the authors provide guidelines for their use. The need for well-designed trials involving children of different age groups is stressed. The data thus obtained might help overcome some of the uncertainties that still exist in the proper management of children with anticoagulants.

Great thanks are expressed to all contributors to this issue. All expertly reviewed the various aspects of pediatric hemostasis and thombosis. Some authors worked directly with Dr. Andrew, others had a close working relationship with her, all admire the many contributions she made to a better understanding of pediatric hematology, clearly reiterating the concept that “children are not little adults.” Special appreciation is expressed to Dr. Andrew's close associate, Lesley Mitchell, M.Sc, for assembling these contributions and for being willing to serve as the guest editor for this issue.